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Prenatal Malaria Immune Experience Affects Acquisition of Plasmodium falciparum Merozoite Surface Protein-1 Invasion Inhibitory Antibodies during Infancy¹

Arlene Dent^*, Indu Malhotra^*, Peter Mungai^*,, Eric Muchiri, Brendan S. Crabb, James W. Kazura^* and Christopher L. King^2,*,

^* Center for Global Health and Diseases, Case Western Reserve University, Cleveland, OH 44106; Division of Vector Borne Diseases, Nairobi, Kenya; Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; and Veterans’ Affairs Medical Center, Cleveland, OH 44106

African infants are often born of mothers infected with malaria during pregnancy. This can result in fetal exposure to malaria-infected erythrocytes or their soluble products with subsequent fetal immune priming or tolerance in utero. We performed a cohort study of 30 newborns from a malaria holoendemic area of Kenya to determine whether T cell sensitization to Plasmodium falciparum merozoite surface protein-1 (MSP-1) at birth correlates with infant development of anti-MSP-1 Abs acquired as a consequence of natural malaria infection. Abs to the 42- and 19-kDa C-terminal processed fragments of MSP-1 were determined by serology and by a functional assay that quantifies invasion inhibition Abs against the MSP-1₁₉ merozoite ligand (MSP-1₁₉ IIA). Infants had detectable IgG and IgM Abs to MSP-1₄₂ and MSP-1₁₉ at 6 mo of age with no significant change by age 24–30 mo. In contrast, MSP-1₁₉ IIA levels increased from 6 to 24–30 mo of age (16–29%, p < 0.01). Infants with evidence of prenatal exposure to malaria (defined by P. falciparum detection in maternal, placental, and/or cord blood compartments) and T cell sensitization at birth (defined by cord blood lymphocyte cytokine responses to MSP-1) showed the greatest age-related increase in MSP-1₁₉ IIA compared with infants with prenatal exposure to malaria but who lacked detectable T cell MSP-1 sensitization. These data suggest that fetal sensitization or tolerance to MSP-1, associated with maternal malaria infection during pregnancy, affects the development of functional Ab responses to MSP-1 during infancy.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the U.S. Department of Health and Human Services (National Institutes of Health (NIH) Grants AI064687 and AI45473) and the Kenyan Ministry of Health. B.S.C. is an International Research Fellow of the Howard Hughes Medical Institute. A.D. was supported by National Institutes of Health Training Fellowships (AI5206702 and AI0702427).

² Address correspondence and reprint requests to Dr. Christopher L. King, Veterans’ Affairs Medical Center, Cleveland, OH 44106. E-mail address: christopher.king{at}case.edu

³ Abbreviations used in this paper: CBL, cord blood lymphocyte; MSP, merozoite surface protein; RTQPCR, real-time quantitative PCR; AU, arbitrary unit.